Environmentally benign synthesis of heterocyclic compounds by combined microwave-assisted heterogeneous catalytic approaches^†

Abstract

Recent advances in the application of heterogeneous catalysis combined with microwave irradiation in the synthesis of heterocyclic compounds are reviewed. While a detailed summary of the different catalysts applied in the synthesis of heterocycles is provided, the work mainly focuses on the heterocyclic compounds and their synthesis and not the preparation or characterization of the catalyst. Due to the large number of N-containing heterocycles, the synthesis of these compounds dominates this account, however, the preparation of other heteroatom containing compounds is also covered in detail. The literature data are summarized based on the size of cycles and the number of heteroatoms in the compounds. Since the major goal of the work is to highlight the environmentally benign and sustainable nature of the combined microwave-assisted heterogeneous catalytic methods, the green aspects of the individual synthetic approaches will be emphasized.

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1. Introduction

Heterocyclic compounds have always been on the forefront of attention due to their numerous uses in pharmaceutical applications.¹ Heterocyclic moieties also serve as an integral part of a broad variety of biologically active natural products and synthetic compounds.² The overwhelming majority of commercially available synthetic drugs (up to 80%) have a heterocyclic structural component.³ Due to the widespread interest in heterocycles, the synthesis of these compounds has always been among the most important research areas in synthetic chemistry, resulting in the development of several classic named reactions.⁴ In many cases, the classic syntheses provide reliable access to heterocyclic compounds, however, they are simply no longer acceptable by current environmental and safety standards. Contemporary developments in discovery and process chemistry emphasize new sustainable synthetic routes, requiring rapid and environmentally acceptable alternatives to the classic methods.⁵ The development of sustainable synthetic procedures to replace the efficient but somewhat outdated classic methods began several decades ago and such methods are still in high demand.

Taking into account the basic principles of green synthesis and the production of chemicals outlined by Anastas and Warner,⁶ various new ecofriendly approaches have been designed. Approaches to address such challenges include the application of non-traditional activation methods, such as microwave irradiation,⁷ sonochemistry,⁸ the use of environmentally benign solvents⁹ and catalysis¹⁰ as major tools in green synthesis and engineering.

Due to the focus of this work, only methods that apply heterogeneous catalysis and microwave activation in a combined manner will be discussed. Both methods were broadly applied in the synthesis of heterocycles. Due to the central role of these compounds in a wide range of applications, several recent reviews summarize the latest developments in microwave-assisted¹¹ as well as heterogeneous catalytic¹² synthesis of heterocycles. The combined applications of these methods were pioneered by Varma in the early 1990s¹³ and later expanded upon by others.¹⁴ The unique combination of solid catalysts with microwave activation resulted in several beneficial features. (i) First, most solid catalysts absorb microwave irradiation, thus they can serve as an internal heat source for the reactions. As all heterogeneous catalytic reactions occur on the surface of catalysts, it is the most direct and selective heating that one can provide. (ii) The catalyst itself can serve as a heat source and as a medium for reactions, eliminating the need to apply a solvent for these reactions. In fact, the use of solvents has an adverse effect on such reactions; the solvent keeps the reactants in the solution phase, making mass transfer an important, often limiting factor. When the compounds are adsorbed on the surface of the catalysts such limitations do not exist, therefore the reactions are significantly more rapid than in solvents (dry or solvent-free reactions). Such terminology, however, is commonly a target for criticism, as the starting materials can be placed on the surface of a catalyst by simple mortar mixing but the products can only be isolated by the use of a solvent. The usual method is to add a small amount of solvent to dissolve the products and then remove the catalyst by filtration. Therefore, only the reaction and not the entire process is solvent-free. Since the use of most organic solvents, especially at high temperatures, represents a fire-hazard, eliminating the solvent during the reaction step when heating occurs is unambiguously beneficial from a green chemistry as well as a safety point of view. (iii) Based on a broad array of literature data heterogeneous catalytic microwave-assited reactions occur much more rapidly than their conventionally heated counterparts, thus the time factor is another advantage.

Whether the application of microwave irradiation in synthesis in itself, makes a process green is the target of an ongoing debate. Authors often claim that the application of microwave heating makes a process green. This is a commonly believed but rarely proven or even studied “axiom” which came under scrutiny in a recent work by Moseley and Kappe.¹⁵ In their critical assessment, the authors pointed out that determining the energy efficiency of microwave-assisted reactions is a complex task and should be evaluated on an individual basis. The authors concluded that microwave heating should not be automatically labeled as green based purely on energy efficiency considerations. While we share this view one cannot fail to notice that all examples, which the authors analyzed were in the solution phase, i.e. homogeneous reactions. Unfortunately, the scope of this work does not allow a detailed discussion of this topic; however, the significant decrease in reaction time, the clearly smaller overall mass heated (no solvent) and the direct energy transformation by the solid catalyst all suggest that the unique combination of heterogeneous catalysis and microwave irradiation would also be more energy efficient than its convectively heated counterpart. A detailed comparative study on this topic is in progress.

Here, we briefly discuss the most common solid catalysts used in microwave-assisted reactions.

1.1. Solid acid–base catalysts

Solid acids are becoming common catalysts for organic synthesis. These materials include a number of Brønsted and Lewis acids and often possess both Brønsted and Lewis acid centers. Solid Brønsted acids include (i) acidic (or cation) ion exchange resins (e.g. Nafion-H, Amberlyst, Dovex, Deloxane etc.), and (ii) heteropoly acids and their derivatives (e.g. H_0.5Cs_2.5[PW₁₂O₄₀]). Solid Lewis acids are usually based on (i) metal chlorides (e.g. ZnCl₂, AlCl₃etc.), or (ii) lanthanide triflates and (iii) sulfated metal oxides (e.g. sulfated zirconia). Perhaps the most common group includes catalysts which possess mixed acidity: (i) clays (e.g. K-10 montmorillonite, KSF-montmorillonite and several modified derivatives, such as ClayFen, ClayCop etc.), (ii) zeolites (e.g. H-Y, H-ZSM and other modified and synthetic zeolites) and (iii) metal oxides (e.g. alumina, mixed oxides etc.). Due to the focus of the present work, catalytic aspects such as catalyst preparation and characterization will not be discussed. There are several excellent accounts on this topic where further details can be obtained.¹⁶

Solid base catalysts are also common, although much less frequently used than solid acids. The most common examples are magnesium oxide, alumina, polyvinyl-pyridine or basic, ion-exchanged clays, hydrotalcites or zeolites.¹⁷

1.2. Heterogeneous metal catalysts

Heterogeneous metal catalysts are commercially available in numerous forms. Although the metals used are varied by the target reaction, the majority of these catalysts are prepared for hydrogenation reactions. Platinum group metals and nickel are the most commonly used metals; however, inexpensive metals such as copper are also frequently applied, especially in large scale applications.

One particular problem that earlier inhibited the use of solid metal-containing catalysts in microwave reactions is the arcing phenomenon that can create hazardous conditions if flammable solvents are used.¹⁸ Arcing, however, is characteristically linked to large metal particles. Most commonly available supported metal catalysts, however, possess metal particles of nanometer size, ensuring that reactions can be safely carried out, even in organic solvents.¹⁹

The major groups of metal catalysts include unsupported metals, supported metal catalysts, heterogenized metal complexes and metal nanoparticle-based supramolecular complexes. Unsupported metal catalysts include (i) metal oxide based catalysts, e.g. Adams' platinum (PtO₂), (ii) the so-called metal blacks, which are bulk metals,²⁰ and (iii) the group of skeletal metals, which include the RANEY®-type catalysts that are prepared from metal-Al alloys (e.g. Ni–Al alloy).²¹ Most of these catalysts, including the pyrophoric RANEY®-Ni, are commercially available and routinely used by synthetic chemists. (iv) Amorphous metal alloys are used in the form of simple powders (e.g. NiB or NiP) or metallic glasses. These catalyst precursors usually show low activity and are not commonly used in synthetic applications.²²Supported metal catalysts are most frequently used in synthetic chemistry due to their efficacy and economic nature.²³ Using a proper support of indifferent or reactive nature, the metal component is deposited on the surface of a support, usually an inorganic solid. They are chemically inert (e.g. charcoal, C or polystyrene) as well as somewhat reactive (SiO₂, Al₂O₃, zeolites etc.) supports.²⁴Heterogenized metal complexes are the very popular metal complexes covalently anchored to solid supports. They mimic the features of soluble complexes, but are not commonly available commercially, and therefore rarely used in synthetic applications.²⁵ The last major group is the recently introduced nanoparticle-based metal catalysts that are based on metal nanoparticles stabilized by certain supramolecular assemblies, such as cyclodextrins or soluble organic polymers.²⁶

2. Heterocycles with nitrogen as the only heteroatom

2.1. 5-Membered rings containing one nitrogen atom

5-Membered N-heterocycles such as pyrroles, indoles and carbazoles are important structural motifs in an extensive number of biologically active compounds.²⁷ They are of exceptional interest in the pharmaceutical industry, as they appear in the core structure of several drugs.

A novel three-component reaction of phenacyl and vinyl bromides, pyridine and acetylenes for the synthesis of indolizines was developed (Scheme 1).²⁸ The reaction was catalyzed by basic alumina. It was proposed that an N-alkylpyridinium salt was generated in situ from the condensation of the bromo compound and pyridine, and then converted to a 1,3-dipole species under basic conditions. This dipolar intermediate reacts with the acetylene derivative by a dipolar cycloaddition reaction under microwave-assisted solvent-free conditions to form indolizines in excellent yields (87–94%). For comparison, the reactions were carried out under microwave-assisted conditions in dry toluene. It was observed in the case of all substrates that the solvent-free reactions consistently performed better than those carried out in toluene which gave yields ranging from 60–71%.

Scheme 1

A Paal–Knorr type method was described for the synthesis of N-substituted pyrroles via the condensation of primary amines and sulfonamides with 2,5-dimethoxytetrahydrofuran (Scheme 2).²⁹ The material used to catalyze the reaction was an environmentally benign, microwave-active solid-acid (K-10 montmorillonite). Various N-substituted pyrroles were synthesized under solvent-free reaction conditions in very good yields in 3–6 min.

Scheme 2

Hexan-2,5-dione was used as an alkylating agent in a solvent-free solid-acid catalyzed electrophilic annelation reactions for the synthesis of pyrroles, indoles and carbazoles from primary amines, pyrroles and indoles respectively (Scheme 3).³⁰ It was proposed that the transformations occurred by a Paal–Knorr type reaction and the annelation took place by a double alkylation–dehydration sequence. A wide variety of substituted primary amines, pyrroles and indoles were reacted with 2,5-hexandione in solvent-free reactions to obtain the corresponding pyrroles, indoles and carbazoles in excellent yields.

Scheme 3

In a follow up study, Kulkarni et al. investigated the use of alcohols as alkylating agents for the alkylation of indoles using K-10 (Scheme 4).³¹ A tertiary alcohol, t-butyl alcohol, was used as an alkylating agent to obtain C-3 alkylated products selectively. The study was also extended to investigate the use of hexan-2,5-diol, which underwent C-3 selective Friedel–Crafts alkylation followed by a secondary intramolecular Friedel–Crafts alkylation forming a tetrahydrocarbazole intermediate. Under the experimental conditions, the tetrahydrocarbazole intermediate underwent a K-10-catalyzed oxidative aromatization forming 1,4-dimethylcarbazole.

Scheme 4

Varma et al. have synthesized a novel glutathione organocatalyst supported on ferromagnetic nanoparticles.³² The magnetic nanoparticles offer a large surface area to anchor the glutathione organocatalyst. An added advantage of these nanoparticles is that they can be magnetically separated from the reaction mixture with minimal effort and be recycled in subsequent reactions. The novel anchored organocatalyst was synthesized by sonicating Fe₂O₃ nanoparticles with glutathione in water at room temperature (Scheme 5).

Scheme 5

This newly synthesized material was tested as a nano-organocatalyst in the Paal–Knorr reaction of various substituted primary amines with 2,5-dimethoxytetrahydrofuran (Scheme 6).³³ The corresponding pyrroles were obtained in good yields under microwave-assisted, aqueous conditions.

Scheme 6

The same catalyst was also employed in the synthesis of pyrazoles by a double condensation reaction of phenylhydrazine with substituted 2,4-pentanediones under microwave-assisted aqueous conditions (Scheme 7).³³

Scheme 7

In both cases (Schemes 6 and 7), the catalyst was magnetically separated from the reaction mixtures and reused up to three times without any loss of catalytic activity.

1,2,3,4-Tetrasubstituted pyrroles were synthesized by a SiO₂-catalyzed double domino reaction of conjugated alkynoates and primary amines³⁴ (Scheme 8). Various polysubstituted pyrroles were synthesized in a one-pot fashion. While the reaction takes months to proceed at room temperature and hours under conventional heating conditions, it occurs in 8 min under microwave-assisted conditions. The overall reaction is a solvent-free domino sequence involving the formation of an 1,3-oxazolidine intermediate and its subsequent intramolecular rearrangement to form tetrasubstituted pyrroles. The reported protocol is ideal for diversity-oriented synthesis since a large variety of substituted products can be obtained with the pyrrole backbone under environmentally benign conditions in short reaction times.

Scheme 8

Lipińska described a microwave-induced heterogeneous catalytic Fischer indolization as the key step in the preparation of 9-methoxyindolo[2,3-a]quinolizine from 2-acetylpyridines (Scheme 9).³⁵ In the key step, the hydrazone of 2-acetylpyridine undergoes the Fischer indole reaction to form 2-pyridoindole. The catalyst of choice was K-10 montmorillonite modified with ZnCl₂ (K-10/ZnCl₂). The new catalyst is significantly greener than the previously reported catalysts for similar transformations.³⁶ Moderate yields were obtained after a reaction time of 2.5 min under microwave-assisted conditions.

Scheme 9

In an extension of this study, Lipińska and Czarnocki described an improved method for the Fischer indolization of phenyl- and methoxyphenyl-hydrazones of various substituted 2-acetylpyridines as shown in Scheme 10.³⁷ This study compared different catalytic conditions viz. K-10/ZnCl₂, K-10/ZnCl₂ with triethylene glycol and ZnCl₂ in triethylene glycol. It was observed that the homogeneous protocol using ZnCl₂ in triethylene glycol was more efficient (up to 52% yield) than the heterogeneous counterpart using K-10 (yields up to 34%)(Scheme 10).

Scheme 10

The Michael addition of electron deficient olefins to pyrroles under solvent-free conditions was reported (Scheme 11).³⁸ The reaction was carried out in presence of silica gel. In the case of hindered olefins, a catalytic amount of BiCl₃ (5 mol%) was added to the reaction mixture. The Michael adducts were obtained in 1–4 min in yields up to 95%.

Scheme 11

A K-10-catalyzed ring-closing Friedel–Crafts reaction was used in one of the key steps in the synthesis of (−)-fischerindole G by Baran and Richter (Scheme 12).³⁹

Scheme 12

Laronze-Cochard et al. investigated the synthesis of 2,4-diaryl substituted carbazoles from tetrahydrocarbazole.⁴⁰ Microwave irradiation of tetrahydrocarbazoles adsorbed on silica gel afforded the corresponding carboxylic acids as a mixture of diastereomers in 71–86% yield. A higher irradiation temperature (200 °C) and longer reaction time permitted a direct transformation of tetrahydrocarbazoles to aromatic carbazoles in moderate yield (41%) by a solvent-free decarboxylation–aromatization domino reaction (Scheme 13).

Scheme 13

2.2. 5-Membered rings containing two nitrogen atoms

Substituted pyrazoles and imidazoles constitute the building blocks of a large number of pharmaceutical and agrochemical products. Pyrazoles form the core of several drugs such as Zometapine⁴¹ or Sildenafil.⁴² Compounds containing imidazoles exhibit interesting biological properties such as anti-inflammatory, anti-fungal and analgesic agents.⁴³

1,3,5-Trisubstituted pyrazoles were synthesized from chalcones and hydrazines catalyzed by a Pd/C/K-10 bifunctional catalyst (Scheme 14).⁴⁴ The catalyst was a mechanical mixture of commercially available Pd/C and K-10 montmorillonite. The reaction involved a condensation of chalcones with hydrazines and cyclization. These two steps were catalyzed by K-10. Pd/C ensured high rates in the last aromatization step to form the corresponding 1,3,5-trisubstituted pyrazoles in good to excellent yields (80–98%) as represented in Scheme 14.

Scheme 14

A four component reaction of benzil, ammonium acetate, benzaldehydes and primary amines was applied to synthesize 1,2,4,5-tetrasubstituted imidazoles. The microwave-assisted reaction was catalyzed by HY zeolite or silica gel (Scheme 15(a)).⁴⁵ This solvent-free process produced the target compounds in 6 min in yields higher than those achieved by conventional heating.

Scheme 15

The four-component cyclocondensation to tetrasubstituted imidazoles can also be carried out using a Fe³⁺/K-10 catalyst as reported by Raghuvanshi and Singh (Scheme 15(b)).⁴⁶ The catalyst used in this study is K-10 montmorillonite impregnated with FeCl₃. The products were obtained in good yields in 3–4 min of microwave irradiation under solvent-free conditions.

The synthesis of imidazo[1,2-a] annulated pyridines, pyrazines and pyrimidines was reported by a three component microwave-assisted K-10-catalyzed condensation approach (Scheme 16).⁴⁷ This solvent-free reaction provided the target compounds via the reactions of aldehydes, isocyanides and aromatic amines in a matter of minutes. The products were obtained in yields up to 88%.

Scheme 16

2.3. 5-Membered rings containing three nitrogen atoms

The azide–alkyne Huisgen [3 + 2]-cycloaddition reaction, better known as the “click” reaction, is a highly efficient reaction for the synthesis of triazoles.⁴⁸ The reactions can be catalyzed by Cu(I)- or Cu(II)-species and carried out at ambient or slightly elevated temperatures, but it can take several hours to achieve completion. Although limited in number, there are reports of such cycloaddition reactions catalysed by heterogeneous catalysts.

Lipschutz et al. reported the use of a charcoal supported copper (Cu/C) as a robust heterogeneous and highly regioselective catalyst for the synthesis of 1,2,3-triazoles (Scheme 17(a)).⁴⁹ It was observed that under traditional heating conditions the reaction required one equivalent of base such as triethylamine to ensure high reaction rates. Under microwave conditions, however, the reaction could be carried out quantitatively at 150 °C in 3 min without the use of any external ligand or base.

Scheme 17

The Huisgen [3 + 2]-cycloaddition has also been applied under microwave-assisted conditions using a ligand/additive free Cu–Mn bimetallic heterogeneous catalyst (Scheme 17(b)).⁵⁰ The optimum ratio of Cu : Mn was found to be 2 : 0.25. The click reaction afforded the corresponding 1,4-disubstituted 1,2,3-triazoles from a wide range of substrates in quantitative yields under microwave-assisted conditions. The catalyst was easily removed by filtration after the reaction and reused up to nine times without significant loss of its activity.

In another example, Taran et al. have reported the use of Cu(I)-species anchored to functionalized chitosan microspheres (Scheme 18).⁵¹ Only a 0.1 mol% catalyst loading was required to obtain 1,4-substitued triazoles in quantitative yields at 150 °C in 15 min. All heterogeneous copper catalysts discussed in this section contain copper in the form of Cu(I).

Scheme 18

2.4. 6-Membered rings containing one nitrogen atom

Substituted pyridines exhibit a broad range of biological activity. They are used to modulate hypertension, angina pectoris, act as Ca²⁺-channel blockers and are anti-diabetic, heptaprotective and show anti-tumor properties.⁵² The fused quinoline moiety is also present in an extensive number of naturally occurring and biologically active compounds and also shows interesting photochemical properties.⁵³ In addition, pyridine derivatives are also used as organic bases and organocatalysts in organic synthesis.

A multicomponent reaction of aromatic aldehydes, malononitrile and thiophenols was applied for the one-step synthesis of highly functionalized pyridines (Scheme 19).⁵⁴ The reaction was catalyzed by KF impregnated alumina. The yields were good in the case of the benzaldehydes, as they have both electron-donating and electron-withdrawing substituents. The authors, however, observed that aliphatic or heterocyclic aldehydes did not undergo the reaction with satisfactory yields. For comparison, the reactions were also carried out under conventionally heated reflux conditions in ethanol using an oil bath. The microwave-assisted reactions consistently gave better results (62–93% yields) when compared to the reactions with conventional heating under ethanol reflux conditions (56–82% yields).

Scheme 19

Syntheses of 2,3-disubstituted-6-aryl pyridines and 7,7-dimethyl-2-aryl-5,6,7,8-tetrahydroquinoline-5-ones were achieved efficiently in a solvent-free reaction catalyzed by a potassium dodecatungstocobaltate trihydrate catalyst (1 mol% catalyst loading) and a strong heteropoly acid (Scheme 20).⁵⁵ The target compounds were synthesized by the condensation of enaminones and cyclic/acyclic 1,3-diketones in excellent yields in 3–6 min.

Scheme 20

A metal-free synthesis of pentasubstituted, functionalized polyhydroquinoline derivatives was recently developed via a four component Hantzsch condensation reaction under microwave irradiation (Scheme 21(a)).⁵⁶ The reaction was catalyzed by a novel heterogeneous organocatalyst, glycine, with only 10 mol% catalyst loading. The reaction gave the products in very short reaction times (1–3 min). For comparison, the authors carried out the reaction under traditional oil bath based reflux conditions (80% yield) and also at room temperature (63% yield). Again, the microwave-assisted reactions performed much better in terms of reaction times and yields than their conventional counterparts.

Scheme 21

The Hantzsch condensation reaction has also been carried out with a heterogeneous Ni nanoparticle catalyst (particle size = 80 ± 0.5 nm) under solvent-free reaction conditions (Scheme 21(b)).⁵⁷ The corresponding polyhydroquinolines were obtained in excellent yields in reaction times of 1–1.5 min. The authors also studied the reuse of the catalyst by recycling it in five subsequent reactions. The Ni nanoparticles showed no signs of deactivation after five runs.

In a unified version of the Hantzsch condensation reaction, the subsequent aromatization and the use of the Pd/C/K-10 catalyst (vide supra) was examined in a condensation–aromatization domino sequence in a one-pot synthesis of substituted pyridines using ethyl acetoacetate, ammonium formate and aliphatic/aromatic aldehydes (Scheme 22).⁵⁸ The cyclization readily took place on the surface of the K-10 catalyst, whereas Pd/C dehydrogenated the dihydropyridine intermediates to the corresponding aromatic products.

Scheme 22

As an extension to the one-step synthesis of pyridines, the bifunctional Pd/C/K-10 catalyst was also applied in a one-step synthesis of β-carbolines starting with tryptamines and carbonyl compounds such as benzaldehyhdes and aromatic glyoxals,⁵⁹ respectively (Scheme 23). The final products were formed by a one-pot, three-step domino sequence. In the first step, the aldehyde/glyoxal condensed with the primary amino group of the tryptamine to form an imine. In the second step, the imine underwent a K-10-catalyzed Pictet–Spengler cyclization reaction. In the third and final step, the tetrahydro-β-carboline intermediate underwent a Pd/C-catalyzed dehydrogenation to form β-carbolines in good to excellent yields.

Scheme 23

An efficient route to 2,4-diarylquinolines has been developed by the same group (Scheme 24).⁶⁰ Various 2,4-disubstituted quinolines were synthesized by a three component reaction of anilines, benzaldehydes and terminal phenylacetylenes in the presence of K-10 montmorillonite under solvent-free conditions. Practically any combination of the three components could be used to synthesize the corresponding 2,4-diarylquinolines. The catalyst could be recycled; the catalytic activity was unaltered even after five cycles.

Scheme 24

Recently, the synthesis of 2,4-disubstituted quinolines was achieved by cyclocondensation of 2-aminoarylketones and terminal phenylacetylenes in presence of a K₅CoW₁₂O₄₀·3H₂O catalyst in a solvent-free reaction (Scheme 25).⁶¹ All products were obtained in high yields (75–96%) after 10–20 min of microwave irradiation at 110–120 °C.

Scheme 25

A modified Doebner–Miller synthesis of quinolines from substituted cinnamaldehydes and anilines was also recently reported.⁶² In the one-pot cyclization–aromatization domino approach, K-10 ensured the condensation and cyclization of anilines with cinnamaldehydes and also promoted the aromatization to the final product (Scheme 26). The products were obtained in yields ranging from 40–95% in 4–8 min.

Scheme 26

A highly diastereoselective three component aza–Diels–Alder reaction of benzaldehydes, anilines and cyclohexenone was recently described for the synthesis of azabicyclo[2.2.2]octan-5-ones (Scheme 27).⁶³ The reaction was catalyzed by H₄[SiW₁₂O₄₀], a strong heteropoly acid. The corresponding bicyclic products were obtained in moderate yields in excellent diastereoselectivities (up to >99 : 1).

Scheme 27

In a convenient synthesis of symmetrical and unsymmetrical bipyridines by cross coupling reactions Moore et al. illustrated the use of heterogeneous Ni and Pd catalysts under microwave-assisted conditions (Scheme 28).⁶⁴ In the case of Ni catalysis, the most practical conditions involved Ni/Al₂O₃–SiO₂ (50 mol% loading) with no phosphine ligand. Yields were moderate under Pd-catalysis; however, only 5 mol% catalyst loading was required.

Scheme 28

2.5 6-Membered rings containing two nitrogen atoms

6-Membered aromatic rings containing two nitrogen atoms, such as phthalazinones, quinazolinones, pyrimidines and pyrimidinones, possess a broad spectrum of biological activities and are therefore of interest as target compounds in pharmaceutical and medicinal chemistry.⁶⁵

Phthalaldehydic acid and hydrazines can be coupled to synthesize phthalazinones.⁶⁶ A simple example of this strategy (Scheme 29), consists of a K-10 montmorillonite-catalyzed solvent-free reaction of phthalaldehydic acid and opianic acid with aliphatic or aromatic hydrazines. The corresponding phthalazinones were obtained in good yields after microwave irradiation for 1–35 min.

Scheme 29

A one-pot synthesis of 2,3-disubstituted 4-(3H)-quinazolinones was developed by a multicomponent coupling of isatoic anhydride/anthranilic acid, ortho-esters and amines in the presence of Nafion-H as a heterogeneous catalyst (Scheme 30).⁶⁷ The products were obtained in 2–6 min under solvent-free conditions in good yields. The reaction can tolerate a wide substitution pattern on the ortho-ester and the aniline components.

Scheme 30

As shown in Scheme 31, a green approach was developed for the synthesis of morpholinopyrimidines, starting with benzaldehyde, 1-(4-morpholinophenyl)ethanone and guanidine hydrochloride in the presence of catalytic amount of a heterogeneous NaHSO₄·SiO₂ catalyst.⁶⁸ In the first step of the mechanism, (E)-1-(4-morpholinophenyl)-3-arylprop-2-en-1-one was formed by the condensation of the three components, which was followed by its rearrangement to morpholinophenyl pyrimidines.

Scheme 31

Sulfated zirconia (ZrO₂/SO₄²⁻) was used as a solid, reusable acid for catalyzing the three-component cyclocondensation reaction of β-dicarbonyl compounds with urea/thiourea and substituted aromatic aldehydes to synthesize 3,4-dihydropyrimidin-2(1H)-ones and -thiones (Scheme 32(a)).⁶⁹ The products were obtained in moderate to good yields in a matter of seconds. The catalyst was recycled up to 8 times. Although the catalyst was still active during the 8th run, its activity dropped to almost 50% of the original reactivity.

Scheme 32

In a Biginelli reaction, a series of 3,4-dihydropyrimidones were synthesized using poly(ethylene glycol)-bound sulfonic acid (PEG–SO₃H) as a catalyst under microwave heating (Scheme 32 (b)).⁷⁰ The functionalized poly(ethylene glycol) simultaneously acted as a catalyst and as a solvent in the condensation. The products were obtained after a reaction time of 6 min in good yields and high selectivities.

2.6 6-Membered rings containing three nitrogen atoms

1,3,5-Triazines are used as templates in supramolecular chemistry and dendrimer synthesis, due to their C₃ symmetric core structure.⁷¹

Synthesis of symmetrically substituted 1,3,5-triazines was performed by cyclotrimerization of nitriles under solvent-free conditions using silica-supported Lewis acids as catalysts (Scheme 33).⁷² The catalysts used in these reactions were Lewis acids, such as ZnCl₂, AlCl₃ and TiCl₄, supported on silica gel. Piperidine or morpholine were used as promoters for the cyclotrimerization reactions. Although the microwave-assisted reactions gave good results in short times (1 h), the reactions under conventional conditions over a period of 24 h gave higher isolated yields (up to 84%).

Scheme 33

The preparation of substituted quinazolines was achieved by a microwave-assisted ZnCl₂-catalyzed annulation of oxime ethers with aldehydes (Scheme 34). High yields of quinazolines were obtained with aliphatic aldehydes and aromatic aldehydes bearing electron-withdrawing substituents in the 4-position. The yields were lower using aryl aldehydes with electron-donating substituents. Applying ketones as carbonyl compounds dihydroquinazolines were obtained in poor yields.⁷³

Scheme 34

2.7 7- And higher membered nitrogen containing rings

7-Membered nitrogen containing compounds, e.g. benzodiazepines, show interesting anticancer properties and inhibit HIV-1 reverse transcriptase.⁷⁴

1,5-Benzodiazepines can be efficiently synthesized from the condensation reaction of o-phenylenediamines with ketones. This reaction was extensively explored under microwave-assisted heterogeneous catalytic conditions using various acid catalysts. Scheme 35 summarizes the recent developments in this area.

Scheme 35

Chari and Syamasundar used polyvinylpyridine (PVP) supported ferric chloride as a catalyst (Scheme 35(a)).⁷⁵ Various ketones reacted smoothly with o-phenylenediamines under these reaction conditions to give the corresponding 1,5-benzodiazepine derivatives in excellent yields. Scheme 35(b) shows the synthesis of 1,5-benzodiazepines catalyzed by silica gel supported sodium hydrogen sulfate under solvent-free conditions.⁷⁶ The products were obtained in excellent yields after microwave irradiation for 0.5–1 min.

Benzodiazepines were also synthesized using the K-10 montmorillonite catalyst in the absence of solvents as shown in Scheme 35(c).⁷⁷ In addition, the synthesis of benzimidazoles and quinoxalinones was also reported in the same study. The authors explored the condensation reactions of o-phenylenediamines with ketones, aldehydes and α-ketoesters under K-10-catalyzed microwave-assisted solvent-free conditions. In most cases the products were obtained in high yields in good selectivities and short reaction times (1–6 min for benzimidazoles and benzodiazepines, and 3–55 min for quinoxalinones).

Diversity-oriented synthesis of dibenzoazocines and dibenzoazepines was investigated under microwave-assisted conditions by Bariwal et al. (Scheme 36).⁷⁸ A variety of 6,7-dihydro-5H-dibenzo[c,e]azepines and 5,6,7,8-tetrahydro-dibenzo[c,e]azocines were synthesized by a microwave-assisted copper-catalyzed intramolecular-coupling reaction. Although the reaction occurred more efficiently when a homogeneous CuBr catalyst was used (up to 95% yield), it can also be catalyzed by a heterogeneous Cu/C catalyst after irradiating the reaction mixture for 25 min at 100 °C to obtain the desired product in 82% yield. The use of a heterogeneous Cu/C catalyst enabled the authors to perform the reaction in a continuous flow process at 150 °C to obtain the products in isolated yields up to 79%.

Scheme 36

Conesa et al. investigated the Beckmann rearrangement of cyclododecanone oxime for the selective synthesis of ω-laurolactam (Scheme 37) which is a monomer used for the production of nylon-12.⁷⁹ The authors studied the effect of different heterogeneous catalysts on the outcome of the Beckmann rearrangement. Various solid acids were found to be active and selective, and the desired product was formed in 5 min. The reaction gave a selectivity of 97% and conversion of 94% in the presence of an aluminated mesoporous silica (Al-SBA-15) catalyst in chlorobenzene as a solvent. Under solvent-free conditions, the optimised parameters gave a selectivity of 84% and conversion of 95% towards the desired product.

Scheme 37

3. Synthesis of oxygen-containing heterocycles

3.1. 3-Membered ring systems

Oxiranes or epoxides are versatile reagents in organic chemistry because these systems can be easily created, and readily react in a highly selective manner.⁸⁰ This motif is also present in many biologically important compounds.⁸¹ Epoxides are easily prepared by the reaction of alkenes with peracids⁸² or under strongly alkaline conditions using bases such as NaOH, KOH and Na₂CO₃ , with H₂O₂ as an oxidant.⁸³ Dimethyldioxirane (DMDO), a mild oxidation reagent, was also used for the epoxidation of alkenes in the last three decades.⁸⁴ Another particular advantage of using DMDO is that the only by-product of the oxidation is acetone, a fairly innocuous and volatile compound. However, DMDO is not commercially available because of its instability and the known preparation of DMDO is rather inefficient (typical yields <3%). Varma and co-workers investigated the microwave-assisted epoxidation of cyclic and acyclic olefins over hydrotalcite catalysts in acetonitrile in the presence of hydrogen peroxide (Scheme 38).⁸¹ The protocol provided a rapid and selective process resulting in excellent yields (up to 100%) and were applicable to a wide variety of substrates. Luque et al. used a solid vanadated mesoporous silica (V-SBA-15) for the epoxidation of alkenes under both microwave and conventional heating conditions.⁸⁵ Microwave experiments demonstrated that the long reaction times (12–24 h) required under conventional heating could be reduced to a few minutes (15–60 min) with improved activities and selectivities under similar reaction conditions. The same group prepared stable mesoporous organotitanium silicates and found this material to be very active and selective in the oxidation of various alkenes to epoxides under microwave irradiation using hydrogen peroxide as an oxidant.⁸⁶ The authors also reported the catalyst being highly stable and reusable up to four times preserving over 90% of its initial activity.

Scheme 38

Luque et al. investigated the selective oxidation of cyclohexene under microwave conditions using an SBA15 immobilized Co–salen-complex as a catalyst (Scheme 39).⁸⁷ It was reported that depending on the reaction conditions, the epoxide (65% conversion, 75% selectivity), the cyclohex-2-en-1-ol (70% conversion, 80% selectivity) or the cyclohex-2-en-1-one (>99% conversion, 89% selectivity) could be obtained in a short reaction time (1 to 20 min). The reported solvent-free microwave protocol was simple, greener and more efficient than any other reported cyclohexene oxidation.

Scheme 39

The epoxidation of various cyclic olefins was studied over a carbon templated mesoporous TS-1 under microwave irradiation. The epoxidation of cyclooctene and cyclododecene exhibited good shape-selectivity in contrast to the epoxidation of cyclohexene.⁸⁸

Most procedures for the oxidation of organic substrates use transition metal salts such as Cr(VI), Mn(VII), Mn(IV), Pb(IV) and Ag(I) salts. However, elevated reaction temperatures and basic or acidic conditions can promote undesired side reactions especially in the presence of other sensitive functional groups. Furthermore, a large excess of oxidant is usually required to ensure adequate efficiency and serious environmental problems may arise from the toxicity of heavy metals such as Cr(VI) or Pb(IV). Therefore, many attempts have been made to eliminate these disadvantages, leading to the development of new, catalytic and benign methods. Attempts included the incorporation of transition metal compounds (Ti, V, Cr, Mn, etc.) into inorganic supports, such as montmorillonites and zeolites. Scettri et al. investigated the microwave-assisted oxidation of a series of allylic alcohols with t-butyl hydroperoxide (TBHP) on a zeolite catalyst.⁸⁹ The authors reported a simple, inexpensive and environmentally safe oxidation, which can be considered of synthetic value due to the short reaction times, solvent-free conditions and the satisfactory chemo-, regio- and diastereoselectivities (Scheme 40).

Scheme 40

The epoxidation reaction of an allylic diene was investigated with a titanium binaphthyl-bridged Schiff base complex and t-butyl hydroperoxide (TBHP) (Scheme 41). Using only 0.5 mol% of the complex, the epoxyalcohols were obtained in very high regio-, chemo- and diastereoselectivities under a solvent-free microwave-assisted conditions (Scheme 41).⁹⁰

Scheme 41

3.2. 5-Membered ring systems

The most widely used approach for the synthesis of furans is the Paal–Knorr method in which 1,4-dicarbonyl compounds are converted to furan derivatives via an acid mediated cyclodehydration. Rao and Jothilingam reported that 2-ene-1,4-diones and 2-yne-1,4-diones can be converted to furan derivatives using formic acid and Pd/C in poly(ethylene glycol)-200 (PEG-200) under microwave irradiation.⁹¹ The reaction required less than 5 min, was amenable to scale-up, and worked well for the preparation of both 2,5-diaryl- and 2,3,5-triphenylfuran derivatives. In some cases, catalytic quantity of concentrated H₂SO₄ was required to promote the cyclodehydration step (Scheme 42).

Scheme 42

The catalytic dehydration of fructose, a renewable feedstock, to 5-hydroxymethylfurfural (5-HMF) by microwave heating in acetone–water mixtures in the presence of a cation exchange resin or zeolites as catalysts was reported by Qi et al.⁹² It was shown that the use of an acetone–water medium resulted in yields of 5-HMF up to 73% with 94% conversion at 150 °C (Scheme 43).

Scheme 43

Benzofurans have attracted considerable interest due to their biological activity and their presence in a variety of natural products.⁹³ The 2-aroylbenzo[b]furans were readily obtained from salicylaldehydes and α-tosyloxyketones in the presence of KF–Al₂O₃ in excellent yields, up to 96% (Scheme 44).⁹⁴

Scheme 44

A one-pot synthesis of functionalized benzofurans was developed via O-alkylation, carbon–carbon coupling/cyclization, and dehydration olefination tandem reactions from phenols and phenacyl bromide. The reactions were carried out under microwave irradiation and solvent-free conditions in the presence of alumina supported inorganic bases. Formation of ethers as by-products were also reported (Scheme 45).⁹⁵

Scheme 45

Kabalka and co-workers reported a microwave-enhanced, solvent-free Mannich condensation–cyclization sequence involving the reaction of 2-ethynylphenol with secondary amines and paraformaldehyde on CuI doped alumina in the absence of solvents. The procedure provided 2-(dialkylaminomethyl)benzo[b]furans in good yields. The synthesis of symmetric bis-benzofuran analogue by using cyclic diamine was also reported.⁹⁶ (Scheme 46).

Scheme 46

The same research group investigated the solvent-free microwave-enhanced Sonogashira coupling of iodophenol with terminal alkynes on potassium fluoride doped alumina that yielded benzofurans (Scheme 47). The reaction of o-ethynylphenols with alkyl or aryl iodides resulted in the formation of substituted benzofurans in moderate yields.⁹⁷

Scheme 47

A microwave-assisted zeolite-catalyzed reaction of enaminone with naphthoquinone afforded the naphthofuran derivative in 76% yield (Scheme 48).⁹⁸

Scheme 48

An optimized procedure for the microwave-assisted synthesis of alkyl D-glucofuranosidurono-6,3-lactones was reported by Richel and co-workers.⁹⁹ This one-step protocol involves a direct coupling between a completely O-unprotected D-glucuronic acid and methanol in the presence of solid acid catalysts. The method was solvent-free and offered attractive features, such as short reaction times, high yields, easy set-up and work-up procedures (Scheme 49).

Scheme 49

A simple and efficient procedure for the synthesis of 2-hydroxyimino-3-substituted-tetrahydrobenzofuran derivatives was carried out in the presence of silica gel by Barange et al.¹⁰⁰ Cyclic 1,3-dicarbonyl compounds reacted smoothly with various nitroolefins to furnish hydroxyiminotetrahydro-benzofuran derivatives as a mixture of E and Z isomers (Scheme 50).

Scheme 50

A solid acid-catalyzed microwave-assisted synthesis of isobenzofuran-1(3H)-ones was performed by Landge et al. (Scheme 51). K-10 montmorillonite appeared to be an excellent catalyst for this condensation and successive lactonization reactions. Reaction of phthalaldehydic acid (2-carboxybenzaldehyde) with methylaryl and cyclic ketones was initiated by microwave irradiation and occurred in one reaction vessel. The reactions were completed in 10–30 min providing excellent yields (90–98%).¹⁰¹

Scheme 51

Microwave-assisted rapid and selective synthesis of cyclic carbonates from phenyl glycidyl ether (PGE) and CO₂ was developed using homogeneous and heterogeneous silica supported ionic liquids (SSILs).¹⁰² Unlike the conventional reaction, the microwave heating was successful in producing cyclic carbonate, rather than the mixture of cyclic and oligomer products (Scheme 52).

Scheme 52

3.3. 6-Membered ring systems

Research on pyran derivatives is of great interest in organic synthesis as the pyran ring occurs in a number of natural products.¹⁰³ Pyran derivatives posses a wide range of biological activity and pharmacological properties, such as anti-cancer anti-hypertensive activity.¹⁰⁴ In recent years, several studies were published concerning the environmentally benign synthesis of pyran derivatives by microwave-assisted heterogeneous catalysis. Peng and Song developed an efficient and clean approach for the synthesis of 4H-pyrans in ionic liquid (aqueous 1-methyl-3-(2-aminoethyl)imidazolium hexafluorophosphate) [2-aemim][PF₆] under microwave conditions.¹⁰⁵ The operational simplicity, green reaction medium, reusable catalyst ([2-aemim][PF₆]) as well as good yields in short reaction times makes the procedure an economically valuable and environmentally friendly alternative to conventional methods for the synthesis of the target compounds (Scheme 53).

Scheme 53

Two or three-component cyclocondensations are common for the construction of pyrane rings. Dimedon is one of the starting materials for all the reaction designs. Additional reagents and catalysts used to obtain pyran rings (Scheme 54) are as follows; benzaldehyde derivatives with a FeCl₃–SiO₂ catalyst,¹⁰⁶ chalcone units with a InCl₃·3H₂O catalyst,¹⁰⁷ aryl aldehydes and alkyl nitriles with a NaBr catalyst,¹⁰⁸ aryl aldehyde and alkyl nitriles with a N,N-diethyl amino-propilated silica (NDEAP) catalyst¹⁰⁹ and benzylidenemalononitriles with silica catalyst.¹¹⁰

Scheme 54

Nagarapu et al. developed a simple and efficient procedure for the preparation of aryl-14H-dibenzo[a.j]xanthenes by a one-pot condensation of β-naphthol and aryl aldehydes in the presence of potassium dodecatungstocobaltate trihydrate (K₅CoW₁₂O₄₀·3H₂O), as a heterogeneous catalyst in a solvent-free reaction using microwave irradiation. The method offers several advantages such as excellent yields, simple procedure, short reaction times and milder conditions and the catalyst was found to exhibit remarkable activity¹¹¹ upon reuse (Scheme 55).

Scheme 55

Mg/Al hydrotalcite, a solid base catalyst was found to be highly efficient in the synthesis of 2-aminochromenes via the multicomponent reaction of aromatic aldehydes, malononitrile and α-naphthol under microwave conditions (Scheme 56). The reaction was rapid, clean, provided products in high yields and the catalyst was reusable.¹¹²

Scheme 56

An efficient microwave-assisted synthesis of 7-aminocoumarins and was performed via the Pechmann reaction of aminophenols with dimethyl oxaloacetate using graphite/K-10 montmorillonite mixture as the catalyst (Scheme 57). The process was driven by the strong microwave absorption of graphite associated with the acid catalytic role of the clay.¹¹³

Scheme 57

Another microwave-assisted heterogeneous clay catalyst-based coumarin synthesis was reported by Bandgar and co-workers. A rapid, one-pot synthesis of 3-carboxycoumarins from 2-hydroxy- or 2-methoxybenzaldehydes or acetophenones and Meldrum's acid was described using EPZ10, EPZG or natural kaolinite-based clay under solvent-free conditions using focused microwaves (Scheme 58).¹¹⁴

Scheme 58

Pinto et al. reported the synthesis of a pyran derivative using K-10 montmorillonite with microwave irradiation in moderate yield. A broad range of derivatives and conditions were investigated.¹¹⁵Scheme 59 only illustrates one model reaction.

Scheme 59

Varma and Polshettiwar developed an efficient approach to attach the 1,3-dioxane functionality to ketones (Scheme 60).¹¹⁶ The use of commercially available and inexpensive polystyrensulfonic acid (PSSA) as a catalyst and water as a reaction medium are additional ecofriendly advantages of this synthetic protocol.

Scheme 60

4. Synthesis of sulfur containing heterocycles

Cyclic organic sulfur compounds occur naturally in some plant products and are of great importance as components of synthetic pharmaceuticals and dye-stuff.^1,117 Since organic sulfur compounds have become increasingly useful, development of convenient and practical synthetic methods for these compounds are highly desirable.

Thiiranes are the simplest sulfur containing heterocycles that occur in nature. They have been extensively used in the pharmaceutical, polymer, pesticide and herbicide industries.¹¹⁸ Although there are many classical methods for synthesizing thiiranes, these processes involve long reaction times, the use of highly acidic or oxidizing conditions, high-temperature reactions, expensive reagents, despite which they provide poor yields. Further disadvantages include the formation of several by-products due to the rearrangement or polymerization of the oxiranes and the use of moisture sensitive and foul smelling reagents, which must be handled with care. Kaboudin and Norouzi developed an efficient method for the synthesis of thiiranes from epoxides through a one-pot reaction of epoxides with diethyl phosphite in the presence of ammonium acetate or ammonium hydrogen carbonate/sulfur/and acidic alumina under solvent-free conditions using microwave irradiation.¹¹⁸ This reaction was extended by Zeynizadeh and Yeghaneh using Dowex 50WX8 ion-exchange resin under microwave conditions in 75–98% yield (Scheme 61).¹¹⁹

Scheme 61

Substituted 2-aminothiophenes are important intermediates in the synthesis of a variety of agrochemicals, dyes and pharmacologically important compounds.¹²⁰ The most convergent and well-established classical approach for the preparation of 2-aminothiophenes is the Gewald's method, which involves a multicomponent condensation of a ketone with an activated nitrile and elemental sulfur in the presence of morpholine as a catalyst.¹²¹ Sridhar and co-workers¹²⁰ applied KF–alumina as a solid base catalyst for the preparation of 2-aminothiophenes by a microwave accelerated multi-component condensation (Scheme 62). The method is an efficient and convenient modification of the Gewald reaction as it could be carried out in short reaction times under microwave irradiation. Similarly, Huang et al. reported a microwave-assisted synthesis of 2-amino-thiophene-3-carboxylic acid derivatives under solvent-free conditions using the same reagents with silica or alumina as the solid catalyst.¹²²

Scheme 62

Due to their relevant electronic and optical features, oligothiophenes are among the most important and widely studied organic materials. Barbarella and co-workers developed a synthesis of thiophene oligomers under microwave irradiation in the liquid phase¹²³ and under solvent-free conditions.¹²⁴ As an extension, a heterogeneous procedure was reported for the preparation of highly pure thiophene oligomers via microwave-assisted Pd catalysis by using silica- and chitosan-supported Pd complexes.¹²⁵ Their approach was more efficient and greener than the existing homogeneous methodology as it combined a high yield reaction with improved catalyst separation. The microwave-assisted approach afforded the selective preparation of the coupled products in high yields (up to 87% isolated yield, 30–100 min) (Scheme 63).

Scheme 63

5. Synthesis of heterocycles containing more than one type of heteroatom

Cyclic compounds consisting of more than one type of heteroatom have interesting biological properties and are potentially important in medicinal applications.

1,3,4-Oxadiazoles and 1,3,4-thiadiazoles belong to a class of heterocycles, which have attracted significant interest in medicinal chemistry and they have a wide range of pharmaceutical and biological activities including antimicrobial, anti-fungal, anti-inflammatory and anti-hypertensive effects. The widespread use of 1,3,4-oxadiazoles as a scaffold in medicinal chemistry establishes this moiety as an important bioactive class of heterocycles. These molecules are also utilized as pharmacophores due to their favorable metabolic profile and ability to engage in hydrogen bonding.¹²⁶ Varma and Polshettiwar reported a novel one-pot, solvent-free synthesis of 1,3,4-oxadiazoles and 1,3,4-thiadiazoles by the condensation of acid hydrazide and triethylorthoalkanates under microwave irradiation. It was noted that the solvent-free reaction conditions and the use of Nafion NR50 and P₄S₁₀/Al₂O₃ as the catalyst are particularly ecofriendly attributes of this synthetic protocol (Scheme 64).¹²⁷

Scheme 64

A series of symmetrical and unsymmetrical 2,5-disubstituted 1,3,4-oxadiazoles were efficiently synthesized via the cyclodehydration of diacylhydrazines by using silica-supported dichlorophosphate as a recoverable cyclizing–dehydrating agent in a solvent-free system under microwave irradiation. This procedure has several advantages, such as being non-corrosive, and having an accelerated rate, and high yields. It has a simple work-up procedure and no waste is generated (Scheme 65).¹²⁸

Scheme 65

2,5-Disubstituted 1,3,4-oxadiazoles were prepared by the acidic alumina-catalyzed cyclization of acid hydrazides and benzoic acid (Scheme 66).¹²⁹

Scheme 66

2-Aryl-5-(coumarin-3′-yl)-1,3,4-oxadiazoles were synthesized by a microwave accelerated solvent-free procedure in high yields via the condensation of coumarin-3-carboxylic acid with benzoic acid hydrazides using poly(ethylene glycol) (PEG) supported dichlorophosphate as the dehydration reagent.¹³⁰ The authors also noted that the features of the simple work-up procedure; and the utilization of easily prepared and recoverable polymer supported reagents; make this method suitable to high throughput and the combinatorial synthesis of 1,3,4-oxadiazoles (Scheme 67).

Scheme 67

Oxadiazoles possess important biological properties, such as analgesic or anti-inflammatory activities.¹³¹ Kaboudin and co-workers developed two different procedures for the synthesis of 1,2,4-oxadiazole derivatives. Reaction of amidoximes and acyl chlorides with magnesium oxide¹³² or alumina supported ammonium fluoride¹³³ resulted in the formation of 1,2,4-oxadiazole derivatives. In the other method, the authors used alkyl nitriles, acyl chlorides and magnesia-supported hydroxyl amine hydrochloride¹³⁴ or the same reagent in the presence of potassium fluoride¹³⁵ with microwave irradiation (the latter solvent-free), and obtained the target compounds in high yields (Scheme 68).

Scheme 68

The oxazole ring system is a basic building block in several biologically important compounds.¹³⁶ A direct transformation of aromatic ketones into oxazoles in the presence of mercury(II)-acetate under microwave irradiation was described by Lee and Song. It was pointed out that the short reaction time, the high yield, and the simple work-up offer significant advantages over existing methods for the synthesis of multisubstituted oxazole rings (Scheme 69), although the use of a mercury-based catalyst raises questions.¹³⁷

Scheme 69

Thiadiazole derivatives also attracted great attention due to their broad biological activity.¹³⁸ Li and co-workers developed an efficient solvent-free microwave-assisted protocol for preparation of 2-amino-5-substituted 1,3,4-thiadiazoles by using poly(ethylene glycol)-supported dichlorophosphate (PEG-OP(O)Cl₂) as the dehydrating agent (Scheme 70).¹³⁹

Scheme 70

Thiazoles are also known to posses valuable biological activities.¹⁴⁰ Varma et al. developed a new process for the synthesis of 1,3-thiazoles in excellent yields, from thioamides, α-tosyloxyketones and applying K-10 montmorillonite as a solid acid under microwave conditions (Scheme 71).⁹⁴

Scheme 71

A new procedure was developed for the synthesis of bithiazole derivatives. It was based on the condensation of thioamides or thiourea with α-bromo ketones under microwave conditions in the presence of K-10 montmorillonite as a solid acid catalyst (Scheme 72).¹⁴¹

Scheme 72

A mild and efficient method was developed for the preparation of 2-arylbenzothiazoles in the presence of a catalytic amount of Cu_1.5PMo₁₂O₄₀/SiO₂ under microwave-assisted and solvent-free conditions. The catalyst could be reused several times but loss of activity was observed (Scheme 73).¹⁴²

Scheme 73

Substituted benzoxazinone derivatives are important heterocyclic units in numerous biologically active and natural compounds.¹⁴³ Petricci and co-workers¹⁴⁴ developed a cyclohydrocarbonylation process using 2-iodoaniline and acyl chlorides producing benzoxazinones (Scheme 74).

Scheme 74

Benzoxazinone derivatives were synthesized by cyclodehydrazination of salicylaldehyde semicarbazones on K-10 montmorillonite catalyst under microwave-assisted solvent-free conditions¹⁴⁵ (Scheme 75).

Scheme 75

An environmentally friendly procedure for the synthesis of a series of 8-substituted-2-carboxy-2,3-dihydro-1,5-benzothiazepines under solvent-free microwave conditions was described. The results were compared to those obtained with a classical heating method. The authors noted that a proper choice of the reaction conditions yielded the final products in good yields in a one-step procedure, whereas experiments under conventional heating led to benzothiazepines along with other products in low yields with tedious work-ups (Scheme 76).¹⁴⁶

Scheme 76

A solvent-free, microwave-assisted one-pot synthesis of [1,3,4]thiadiazolo[2,3-c][1,2,4]triazinone starting with aromatic aldehydes and triazine derivatives was reported in moderate yields. It was also noted that the reaction was limited to aromatic aldehydes (Scheme 77).¹⁴⁷

Scheme 77

A convenient approach for the preparation of thiazine and thiazole derivatives was achieved by intramolecular dehydrative ring closure of S-hydroxyalkyl imidazoles using potassium carbonate in DMF using both conventional and microwave methods¹⁴⁸ (Scheme 78).

Scheme 78

Yadav and Rai developed a green protocol for an expeditious synthesis of various potentially useful bicyclic hetereocycles starting with readily available substrates employing solvent-free microwave irradiation conditions (Scheme 79).¹⁴⁹

Scheme 79

Yadav and Kapoor reported a clay-catalyzed, atom- and energy-efficient, rapid one-pot synthesis of thiazine derivatives from readily available substrates (chalcones and cyclic thioureas) employing solvent-free microwave activation (Scheme 80).¹⁵⁰

Scheme 80

A novel and ecofriendly method for the synthesis of thiazolo[3,2-b][1,2,4]-triazoles from 3-mercapto-[1,2,4]-triazole and allyl bromide in the presence of acidic silica was also reported (Scheme 81).¹⁵¹

Scheme 81

Yadav et al. developed a diversity-oriented synthetic approach for the preparation of various 1,3-oxazin-2-one-(thione)-fused N- and O-heterocyclic systems using D-glucose (Scheme 82) and D-xylose as renewable resources under solvent-free microwave-assisted conditions (Scheme 82).¹⁵²

Scheme 82

A heterogeneous catalytic method for the preparation of 2-substituted 1,3-oxazolines, imidazolines and thiazolines was also recently reported. The use of silica-supported 12-tungstophosphoric acid (TPA–SiO₂) as non-toxic, recoverable and reusable heterogeneous catalyst makes this procedure environmentally friendly and economically advantageous (Scheme 83).¹⁵³

Scheme 83

An intramolecular, domino, Knoevenagel–hetero Diels–Alder reaction sequence was proven to be a useful protocol to prepare polycyclic heterocyclic systems containing coumarin and chromone moieties under mild conditions. Of the various conditions employed, the solvent-free approach using a solid support accelerated by microwaves was found to be the most effective method in achieving high degrees of chemo- and stereoselectivity with a substantial reduction in reaction time (Scheme 84).¹⁵⁴

Scheme 84

Conclusions and Outlook

Since the discovery of the microwave heating approach, with the significant developments in the manufacturing of state-of-the-art, commercially available instruments, microwave-assisted synthesis became a mainstream method in organic chemistry. The application of microwave irradiation became a general activation method of primary importance and most synthetic laboratories possess such instruments. In addition, while heterogeneous catalysis had been known for more than a century, the recent developments in material science resulted in an explosion-like development of new practical solid catalysts. The combination of these two well-established approaches appear to lead to the development of effective, rapid, and most of all, environmentally benign synthetic methods. The present work illustrates the advantages of microwave-assisted heterogeneous catalysis in the synthesis of heterocycles; compounds that generate great attention in many applications, particularly in medicinal chemistry and drug development. As the pharmaceutical industry is among the environmentally most problematic branches of the chemical enterprise, it is essential that such green synthesis methods become available for the synthesis of heterocycles. Based on the progress summarized in this work, we feel certain that combined microwave-assisted heterogeneous catalytic approaches will find broad applications and will continue to attract much attention in organic synthesis applications.

Acknowledgements

Financial support provided by the University of Massachussetts Boston is gratefully acknowledged. A.D. also thanks The Turkish Council of Higher Education (YÖK) for a fellowship to support his visiting professorship in Boston.

Notes and references

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